Tau is a microtubule-associated protein that is the primary component of neurofibrillary tangles in Alzheimer's disease. Several other neurodegenerative disorders also exhibit abnormal tau lesions and mutations in the tau gene cause some of these diseases. The mechanisms underlying the formation of neurofibrillary tangles are unknown, as are the mechanisms through which mutations in the tau gene cause neurodegenerative disease. Tau's primary known function has been to stabilize and promote microtubule assembly. However, neurons have several microtubule-associated proteins endowed with similar properties and yet tau is uniquely associated with neurodegenerative disease. Similarly, tau is uniquely associated with axonal development although the basis for its role in the acquisition of neuronal cell polarity is not understood. Therefore, unique properties of tau may be responsible for its role in axonal development and neurodegenerative disease. Our laboratory has approached these issues by seeking to identify new functions for tau. We have found that the amino terminus of tau is associated with plasma membrane. We have also found that in neuronal cells, tau associates with the src family non-receptor tyrosine kinase fyn and that in vitro, a PXXP motif in tau interacts with the SH3 domain of src family non-receptor tyrosine kinases. In furthering these findings, we have obtained preliminary data suggesting that tau can increase the tyrosine kinase activity of fyn and that tau associates with membrane microdomains, also known as membrane rafts. We propose to (1) determine the effect of the tau-fyn interaction on the tyrosine kinase activity of fyn and on protein tyrosine phosphorylation in neuronal cells, (2) investigate the tyrosine phosphorylation of tau during signal transduction, (3) extend the characterization of tau in membrane rafts and determine if tau's localization in membrane rafts is dependent on fyn, and (4) investigate the role of tau in membrane rafts in neuronal differentiation. We hypothesize that the interaction between tau and fyn takes place in membrane rafts and that this interaction affects fyn activity, thereby affecting signal transduction. Also, given tau's location in membrane rafts, we speculate that the tyrosine phosphorylation of tau might act to transduce extracellular signals. Signal transduction pathways involving tau and A-beta may go awry during neurodegenerative diseases, leading to inappropriate cross talk between pathways that may culminate in abnormal tau phosphorylation and polymerization.